The Structure of Serine Palmitoyltransferase; Gateway to Sphingolipid Biosynthesis

Beverley A. Yard, Lester G. Carter, Kenneth A. Johnson, Ian M. Overton, Mark Dorward, Huanting Liu, Stephen A. McMahon, Muse Oke, Daphné Puech, Geoffrey J. Barton, James H. Naismith, Dominic J. Campopiano (Lead / Corresponding author)

Research output: Contribution to journalArticlepeer-review

85 Citations (Scopus)

Abstract

Sphingolipid biosynthesis commences with the condensation of L-serine and palmitoyl-CoA to produce 3-ketodihydrosphingosine (KDS). This reaction is catalysed by the PLP-dependent enzyme serine palmitoyltransferase (SPT; EC 2.3.1.50), which is a membrane-bound heterodimer (SPT1/SPT2) in eukaryotes such as humans and yeast and a cytoplasmic homodimer in the Gram-negative bacterium Sphingomonas paucimobilis. Unusually, the outer membrane of S. paucimobilis contains glycosphingolipid (GSL) instead of lipopolysaccharide (LPS), and SPT catalyses the first step of the GSL biosynthetic pathway inSave this organism. We report here the crystal structure of the holo-form of S. paucimobilis SPT at 1.3 Å resolution. The enzyme is a symmetrical homodimer with two active sites and a monomeric tertiary structure consisting of three domains. The PLP cofactor is bound covalently to a lysine residue (Lys265) as an internal aldimine/Schiff base and the active site is composed of residues from both subunits, located at the bottom of a deep cleft. Models of the human SPT1/SPT2 heterodimer were generated from the bacterial structure by bioinformatics analysis. Mutations in the human SPT1-encoding subunit have been shown to cause a neuropathological disease known as hereditary sensory and autonomic neuropathy type I (HSAN1). Our models provide an understanding of how these mutations may affect the activity of the enzyme.

Original languageEnglish
Pages (from-to)870-886
Number of pages17
JournalJournal of Molecular Biology
Volume370
Issue number5
DOIs
Publication statusPublished - 27 Jul 2007

Keywords

  • bioinformatics
  • hereditary sensory and autonomic neuropathy type I
  • serine palmitoyltransferase
  • sphingolipids
  • X-ray crystallography

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